It has been demonstrated in African trypanosomes that transferrin (Tf), together with its receptor, is delivered into lysosomes (Grab et al. Eur. J. Cell Biol. 59 398, 1992). We have coupled 14C-Samorin to bovine Tf using 2-azidophenyl glyoxal (APG Pierce), and demonstrate in vitro the potential use of Tf a as novel drug delivery system in Trypanosoma congolense. Samorin-APG-Tf was incubated with either the T. congolense stock IL 1180 (Samorin-sensitive) or IL 3958 (Samorin-resistent). The specific concentration of Samorin/Tf was 429 ng drug/mg Tf. The APG-Tf conjugate without bound drug was used as the control. IL 1180 grew poorly even at Samorin/Tf concentrations as low as 0.12 ng drug/0.14 mg Tf per ml. Free Samorin kills IL 1180 at a dose of 1 ng/ml. Clearly, the efficacy of the drug/Tf complex was as least as effective as free drug alone even in the presence of high amounts of goat serum Tf present in HMI-93 medium (Hirumi et al., J. Protozool. Res. 3 52, l991). The situation with the Samorin resistent T. congolense clone IL 3958 was quite different. This clone is sensitive to the effects of Samorin-APG-Tf at drug concentrations of 10 ng/ml or higher. Surprisingly, the control APG-Tf conjugate was able to inhibit the growth of both IL 1180 and IL 3958, albeit at similarly high Tf concentrations 24.2-48.5 mg APG-Tf/ml. We also coupled Berenil to Tf but were unable to link sufficient quantities of the drug to the protein to make this combination therapueticaly effective. Our finding has far reaching implications in the treatment of human sleeping sickness as Tf is one of the few serum proteins that is able to cross the blood-brain barrier.